Depression in Parkinson's disease

Psychiatric symptoms frequently coexist with idiopathic Parkinson's disease and are often underdiagnosed and poorly treated.¹ Depression and anxiety are the most common psychiatric conditions that accompany Parkinson's disease. A study by Menza et al found that 12 out of 42 patients with Parkinson's disease met the criteria for an anxiety disorder according to the Diagnostic and Statistical Manual and 11 of them had a comorbid depressive disorder.² Recent reviews show that depression is a common and potentially debilitating aspect of Parkinson's disease, affecting 40-50% of patients.^3–5 While its aetiology in Parkinson's disease is unclear (biochemical changes, psychosocial factors, and situational stressors have all been implicated), it has an adverse effect on the quality of patients' lives, and doctors should ensure that it is diagnosed and properly treated.

The diagnosis is not easy because clinical symptoms of depression can overlap with or be mistaken for those of Parkinson's disease (such as the flat affect, inability to work, fatigue, preoccupation with ill health, loss of desire, and reduction in libido. Moreover, depression in patients with Parkinson's disease is qualitatively different from primary major depression in that self blame, guilt, delusions, a sense of failure, self destructive thoughts, and suicide are less frequent.⁷

Several studies have failed to find a clear association between the severity of depression and motor disability. Depressive symptoms precede those of motor dysfunction in 12-37% of patients with Parkinson's disease.⁷ The severity of depression contributes to the cognitive disorders in Parkinson's disease; in a prospective cohort study of patients with Parkinson's disease who did not have dementia, depression was associated with a significantly increased risk of developing dementia.⁹

Depression in Parkinson's disease is usually linked to a reduction in brain catecholamines, serotonin (a decrease in the concentration of 5-hydroxy-indoleacetic acid in cerebrospinal fluid), or dopamine (postmortem studies show dopamine depletion in the ventral tegmental area; glucose positron emission tomography shows hypometabolism in the orbital and prefrontal cortices). Paradoxically, levodopa and dopamine agonists (except selegiline at high doses, 30-40 mg/day) do not consistently alleviate depressive symptoms. In patients with fluctuating motor symptoms depression occurs when motor function is poor; more puzzling, deep brain stimulation, notably of subthalamic nuclei, can induce a delayed depression, although it improves motor function.¹⁰

Once depression is diagnosed, treatment is complicated by the drugs the patient is already taking. Due to the lack of systematic clinical trials there are still three main questions concerning the prescribing of an antidepressant.³,⁴ The first is whether the antidepressant drug can increase or induce parkinsonian symptoms—tricyclic antidepressants such as desipramine, nortriptyline, and imipramine can improve motor symptoms, but selective serotonin reuptake inhibitors are repeatedly reported in case reports as potential inducers of parkinsonism. Fluoxetine is the only one to have been studied in this way, but a retrospective chart review by Caley and Friedman did not find that fluoxetine caused parkinsonian symptoms.⁵ There are no data on the more recently launched antidepressants such as venlafaxine (a serotonin noradrenaline recapture inhibitor) and mirtazapine (a noradrenaline serotonin specific antidepressant).

The second question is the safety of antidepressant drugs in patients with Parkinson's disease. Tricyclic antidepressants can cause delusions, cognitive disorders (due to their anticholinergic effect), or orthostatic hypotension (they block adrenergic alpha receptors). The third question concerns interactions between antidepressant and antiparkinson drugs. Only one drug combination seems to be risky for patients: selective serotonin reuptake inhibitors (such as fluoxetine and fluvoxamine) and selegiline are associated with the potential and rare (the incidence is 0.24%) serotonin syndrome.¹² The diagnosis of serotonin syndrome is made on the basis of three of the following symptoms: a change in mental status (such as the onset of delusions, change in level of consciousness), myoclonus, sweating, hyperreflexia, tremor, diarrhoea, shivering, uncoordination, and fever. This syndrome can be fatal.

The depression associated with Parkinson's disease must be treated. The first choice is selective serotonin reuptake inhibitors (sertraline 50-200 mg/day; paroxetine 20-40 mg/day) or, in some countries and on an empirical basis, tianeptine (12.5 mg three times a day), which increases the presynaptic recapture of 5-hydroxy-indoleacetic acid, or moclobemide (300 mg/day), which is a reversible and selective inhibitor of monoamine-oxidase type. Adverse drug interactions are rare, except when selegiline is given at more than 5 mg twice daily. Clinical trials are needed not only to determine the risk-benefit ratio of these drug regimens but also to determine the optimum dose and duration of antidepressant therapy in Parkinson's disease.